Watersoluble azole antifungals

ABSTRACT

A compound of formula (I), ##STR1## an acid or base addition salt thereof or a stereochemically isomeric form thereof, wherein A and B taken together form --N═CH--, --CH═N--, --CH 2  --CH 2 , CH═CH--, --C(═O)--CH 2  --, --CH 2  --C(═O); D is a radical of formula ##STR2## L is a radical of formula ##STR3## Alk is a C 1-4  alkanediyl radical; R 1  is halo; R 2  is hydrogen or halo; R 3  is hydrogen, C 1-6  alkyl, phenyl or halophenyl; R 4  is hydrogen, C 1-6  alkyl, phenyl or halophenyl; R 5  is hydrogen or C 1-6  alkyl; R 6  is hydrogen, C 1-6  alkyl, C 1-6  alkyloxycarbonyl, or R 5  and R 6  taken together with the nitrogen atom to which they are attached form a heterocyclic ring. Active intermediates, compositions and methods of preparing compounds, compositions are described.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is based upon PCT Application Ser. No. PCT/EP 95/00174,filed Jan. 17, 1995, which is a continuation-in-part of U.S. patentapplication Ser. No. 08/185,352, filed on Jan. 24, 1994, now abandoned.

The present invention is concerned with novel water-solublebroad-spectrum azole antifungals as well as the antifungally activeprecursors thereof.

Systemic fungal infections in man are relatively rare in temperatecountries and many of the fungi that can become pathogenic normally livecommensally in the body or are common in the environment. However, thepast few decades have witnessed an increasing incidence of numerouslife-threatening systemic fungal infections world-wide and these nowrepresent a major threat to many susceptible patients, particularlythose already hospitalized. Most of the increase can be attributed toimproved survival of immunocompromised patients and the chronic use ofantimicrobial agents. Moreover, the flora typical of many common fungalinfections is also changing and this is presenting an epidemiologicalchallenge of increasing importance. Patients at greatest risk includethose with impaired immune functioning, either directly as a result ofimmunosuppression from cytotoxic drugs or HIV infection, or secondary toother debilitating diseases such as cancer, acute leukaemia, invasivesurgical techniques or prolonged exposure to anti-microbial agents. Themost common systemic fungal infections in man are candidosis,aspergillosis, histoplasmosis, coccidioidomycosis,paracoccidioidomycosis, blastomycosis and cryptococcosis.

Antifungals such as ketoconazole, itraconazole and fluconazole are beingincreasingly employed for the treatment and prophylaxis of systemicfungal infections in immunocompromised patients. However, concern aboutfungal resistance to some of these agents, especially the more narrowspectrum ones, e.g. fluconazole, is growing. Worse still, it isrecognized in the medical world that about 40% of the people sufferingfrom severe systemic fungal infections are hardly able, or not at all toreceive medication via oral administration. This inability is due to thefact that such patients are in coma or suffer from severe gastroparesis.Hence the use of insoluble or sparingly soluble antifungals such asitraconazole or saperconazole, that are difficult to administerintravenously, is heavily impeded.

Consequently, there is a need for new antifungals, preferablybroad-spectrum antifungals, against which there is no existingresistance and which can be administered intravenously. Preferably theantifungal should also be available in a pharmaceutical compositionsuitable for oral administration. This enables the physician to continuetreatment with the same drug after the patient has recovered from hiscondition which required intravenous administration of said drug.

U.S. Pat. No. 4,267,179 discloses heterocyclic derivatives of(4-phenylpiperazin-1-yl-aryloxymethyl-1,3-dioxolan-2-yl)-methyl-1H-imidazolesand 1H-1,2,4-triazoles useful as antifungal and antibacterial agents.Said patent encompasses itraconazole, which is now available as abroadspectrum antifungal on a world-wide basis.

U.S. Pat. No. 4,916,134 teaches novel 4- 4- 4-2-(2,4-difluorophenyl)-2-(1H-azolylmethyl)-1,3-dioxolan-4-yl!methoxy!phenyl!-1-piperazinyl!phenyl!triazoloneshaving improved antimicrobial properties. Said patent encompassessaperconazole.

U.S. Pat. No. 4,791,111 discloses derivatives of 4-4-(4-phenyl-1-piperazinyl)phenoxymethyl!-1,3-dioxolan-2-yl!methyl!-1H-imidazolesand 1H-1,2,4-triazoles, structurally related to some of the compounds ofthe present invention, which are taught to have favourableanti-microbial properties.

U.S. Pat. No. 5,039,676 discloses azole-methyl substitutedtetrahydrofurans, structurally related to some of the compounds of thepresent invention, which are taught to have antifungal activity andEP-0,539,938 teaches analogous trisubstituted tetrahydrofuranantifungals.

The present invention concerns novel compounds of formula ##STR4## thepharmaceutically acceptable acid or base addition salts thereof and thestereochemically isomeric forms thereof, wherein

A and B taken together form a bivalent radical of formula:

--N═CH-- (a),

--CH═N-- (b),

--CH₂ --CH₂ -- (c),

--CH═CH-- (d),

--C(═O)--CH₂ -- (e),

--CH₂ --C(═O)-- (f),

wherein one hydrogen atom in the radicals (a) and (b) may be replacedwith a C₁₋₆ -alkyl-radical and up to two hydrogen atoms in radical (c),(d), (e) or (f) may be replaced by a C₁₋₆ -alkyl-radical;

D is a radical of formula ##STR5## L is a radical of formula ##STR6##Alk is a C₁₋₄ alkanediyl radical; R¹ is halo;

R² is hydrogen or halo;

R³ is hydrogen, C₁₋₆ alkyl, phenyl or halophenyl;

R⁴ is hydrogen, C₁₋₆ alkyl, phenyl or halophenyl;

R⁵ is hydrogen or C₁₋₆ alkyl;

R⁶ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkyloxycarbonyl, or

R⁵ and R⁶ taken together with the nitrogen atom to which they areattached form a pyrrolidine, piperidine, morpholine, piperazine orsubstituted piperazine ring, said substituted piperazine being apiperazine ring substituted on the 4-position of the piperazine ringwith C₁₋₆ alkyl, hydroxyC₁₋₆ alkyl, aminoC₁₋₆ alkyl, mono- or di(C₁₋₆alkyl)aminoC₁₋₆ alkyl.

In the definitions hereinabove and hereinafter the term halo definesfluoro, chloro, bromo and iodo; C₁₋₆ alkyl is generic to straight andbranch chained hydrocarbons having from 1 to 6 carbon atoms, such as,for example, methyl, ethyl, propyl, butyl, pentyl or hexyl and thepossible branched isomers thereof; the term "C₁₋₆ alkyl" in C₁₋₆alkyloxy, aminoC₁₋₆ alkyl, mono- and di(C₁₋₆ alkyl)aminoC₁₋₆ alkyl is asdefined hereinabove.

The pharmaceutically acceptable acid addition salts as mentionedhereinabove are meant to comprise the therapeutically active non-toxicacid addition salt forms which the compounds of formula (I) are able toform. The latter can conveniently be obtained by treating the base formwith such appropriate acids as inorganic acids, for example, hydrohalicacids, e.g. hydrochloric, hydrobromic and the like; sulfuric acid;nitric acid; phosphoric acid and the like; or organic acids, forexample, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic,2-oxopropanoic, ethanedioic, propanedioic, butanedioic,(Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic,2,3-dihydroxybutanedioic, 2-hydroxy-1,2,3-propanetricarboxylic,methanesulfonic, ethanesulfonic, benzenesulfonic,4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic,4-amino-2-hydroxybenzoic and the like acids. Conversely the salt formcan be converted by treatment with alkali into the free base form. Thecompounds of formula (I) containing acidic protons may also be convertedinto their therapeutically active non-toxic metal or amine addition saltforms by treatment with appropriate organic and inorganic bases.Appropriate base salt forms comprise, for example, the ammonium salts,the alkali and earth alkaline metal salts, e.g. the lithium, sodium,potassium, magnesium, calcium salts and the like, salts with organicbases, e.g. the benzathine, N-methyl-D-glucamine,2-amino-2-(hydroxymethyl)-1,3-propanediol, hydrabamine salts, and saltswith amino acids such as, for example, arginine, lysine and the like.Conversely the salt form can be converted by treatment with acid intothe free acid form.

The term addition salt also comprises the hydrates and solvent additionforms which the compounds of formula (I) are able to form. Examples ofsuch forms are e.g. hydrates, alcoholates and the like.

The term "stereochemically isomeric forms" as used hereinbefore definesall the possible isomeric forms which the compounds of formula (I) maypossess. Unless otherwise mentioned or indicated, the chemicaldesignation of compounds denotes the mixture of all possiblestereochemically isomeric forms, said mixtures containing alldiastereomers and enantiomers of the basic molecular structure. More inparticular, stereogenic centers may have the R- or S-configuration;substituents on bivalent cyclic saturated hydrocarbon radicals, inparticular the substituents on the dioxolane or tetrahydrofuran ring,may have either the cis- or trans-configuration. Stereochemicallyisomeric forms of the compounds of formula (I) are obviously intended tobe embraced within the scope of this invention.

Alk is appropriately methylene or ethanediyl;

R¹ is suitably fluoro, chloro or bromo, preferably fluoro;

R² is suitably hydrogen, fluoro, chloro or bromo, preferably fluoro;

R³ is suitably hydrogen or phenyl, preferably hydrogen;

R⁴ is suitably hydrogen or phenyl, preferably hydrogen;

R⁵ is suitably hydrogen, methyl or ethyl;

R⁶ is suitably hydrogen, methyl or ethyl; or

R⁵ and R⁶ are suitably taken together with the nitrogen atom to whichthey are attached to form a pyrrolidine ring or a substituted piperazinering.

A and B taken together are suitably radicals of formula (a), (b) or (c).

Interesting compounds are those compounds of formula (I) wherein D is aradical of formula (D₁) or (D₂).

Particular compounds are those compounds of formula (I) wherein L is aradical formula (L₂) wherein R⁵ and R⁶ each independently are hydrogenor C₁₋₆ alkyl; or when taken together with the nitrogen atom to whichthey are attached form a pyrrolidine, or a piperazine ring substitutedwith C₁₋₆ alkyl or C₁₋₆ alkyloxy on the 4-position of the piperazinering.

More interesting compounds are those interesting compounds wherein L isa radical of formula (L₁).

Preferred compounds of formula (I) are those compounds of formula (I)wherein D is a radical of formula (D₁), wherein R¹ is chloro or fluoroand R² is hydrogen, chloro or fluoro; L is a radical of formula (L₁),wherein R³ and R⁴ each independently are phenyl or hydrogen.

The compounds of formula (I) wherein the substituents on the dioxolaneor tetrahydrofuran have the cis-configuration, i.e. wherein thetriazolmethylene substituent and the substituted phenyloxy methylenesubstituent are on the same side of the plane of the dioxolane ortetrahydrofuran ring, are preferred.

More preferred compounds are selected from:

(±)-ammonium cis-1- 4- 4- 4- 4-2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl-methyl)-1,3-dioxolan-4-yl!methoxy!phenyl!-1-piperazinyl!phenyl!-4,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl!methyl!-2,2-dimethylpropylphosphate;

(±)-ammonium cis-1- 4- 4- 4- 4-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-yl-methyl)-1,3-dioxolan-4-yl!methoxy!phenyl!-1-piperazinyl!phenyl!-4,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl!methyl!-2,2-dimethylpropylphosphate;

(±)-ammonium cis-1- 4- 4- 4- 4-2-(4-chlorophenyl)-2-(1H-1,2,4-triazol-1-yl-methyl)-1,3-dioxolan-4-yl!methoxy!phenyl!-1-piperazinyl!phenyl!-4,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl!methyl!-2,2-dimethylpropylphosphate(ester) monohydrate;

(±)-ammonium cis-1- 4- 4- 4- 4-2-(4-fluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl!methoxy!phenyl!-1-piperazinyl!phenyl!-4,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl!methyl!-2,2-dimethylpropylphosphate;

(±)-cis-1- 4- 4- 4- 4-2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl!methoxy!phenyl!-1-piperazinyl!phenyl!-4,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl!methyl!-2,2-dimethylpropyl4-methyl-1-piperazineacetate monohydrochloride; and

(±)-cis-4- 4- 4- 4-2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl!methoxy!phenyl!-1-piperazinyl!phenyl!-2-3,3-dimethyl-2-(phosphonooxy)butyl!-2,4-dihydro-3H-1,2,4-triazol-3-onehemihydrate.

Most preferred is

(±)-cis-4- 4- 4- 4-2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl!methoxy!phenyl!-1-piperazinyl!phenyl!-2-3,3-dimethyl-2-(phosphonooxy)butyl!-2,4-dihydro-3H-1,2,4-triazol-3-one,the stereochemically isomeric forms thereof and the base addition saltsthereof.

The compounds of formula (I) may generally be prepared by O-acylation orO-phosphorylation of an intermediate alcohol of formula (II) with anacylating or phosphorylating reagent of formula (III), wherein W¹ is areactive leaving group such as, hydroxy or halo. Said reaction may beperformed following art-known acylation or phosphorylation procedures,for instance, by stirring the reactants in a reaction-inert solvent,optionally in admixture with a base to pick up the acid that is formedduring the reaction. ##STR7##

The compounds of formula (I) may also be prepared by O-alkylating aphenol of formula (IV) with an alkylating reagent of formula (V),wherein W² is a reactive leaving group such as halo, or a sulfonyloxygroup. Said reaction may be performed by stirring the reactants in areaction-inert solvent, optionally in admixture with a suitable base topick up the acid that is formed during the reaction. In the compoundsand intermediates mentioned hereinafter the substituents are as definedabove, unless otherwise indicated. ##STR8##

The preparation of intermediates of formula (V), wherein D is a radicalof formula D₁, has been disclosed in U.S. Pat. No. 4,267,179. Thepreparation of intermediates of formula (V), wherein D is a radical offormula D₃, has been disclosed in EP-0,539,938.

The compounds of formula (I), wherein L is a radical of formula L₂, saidcompounds being represented by formula (I-b), may also be prepared byO-acylating an intermediate of formula (II) with a reagent of formula(VI) and subsequently reacting the thus obtained intermediate of formula(VII) with an amine of formula (VIII), thus yielding a compound offormula (I-b). ##STR9##

The compounds of formula (I) may also be converted into each otherfollowing art-known transformations. For instance, the compounds whereinL is a radical of formula L₁, said compounds being represented byformula (I-a), may be interconverted as follows. Compounds of formula(I-a) wherein R³ and/or R⁴ are C₁₋₆ alkyl, phenyl or halophenyl may betransformed into compounds of formula (I-a), wherein R³ and/or R⁴ arehydrogen using art-known hydrolysis procedures, e.g. by reaction withsodium hydroxide in an appropriate solvent, e.g. water or 1,4-dioxane.The compounds of formula (I-b) may be interconverted into each other asfollows.

Compounds of formula (I-b) wherein R⁵ and/or R⁶ are hydrogen may betransformed into compounds of formula (I-b), wherein R⁵ and/or R⁶ areC₁₋₆ -alkyl, by art-known N-alkylation reactions. Compounds of formula(I-b), wherein R⁶ is hydrogen may be converted into compounds of formula(I-b), wherein R⁶ is C₁₋₆ alkyloxycarbonyl by art-known N-acylationreactions. Conversely compounds of formula (I-b), wherein R⁶ is C₁₋₆alkyloxycarbonyl may be converted into compounds of formula (I-b),wherein R⁶ is hydrogen by art-known hydrolysis reactions.

The intermediates of formula (II) may be prepared by O-alkylating areagent of formula (IX) with an alkylating reagent of formula (V)following O-alkylation procedures described hereinabove for thepreparation of compounds of formula (I). ##STR10##

The intermediates of formula (II) may also be prepared by O-alkylating areagent of formula (X) with an alkylating reagent of formula (V)following O-alkylation procedures described hereinabove for thepreparation of compounds of formula (I), and subsequently reducing thethus formed intermediate of formula (XI). Said reduction may beperformed by stirring the intermediate of formula (XI) with a reducingreagent, such as, for example, sodiumborohydride in a reaction-inertsolvent, such as, for example, a halogenated hydrocarbon, e.g.dichloromethane, an alcohol, e.g. methanol and mixtures thereof.##STR11##

The preparation of intermediates of formula (X) is disclosed in U.S.Pat. No. 4,931,444.

The intermediates of formula (XI) may also be prepared by N-alkylatingan intermediate of formula (XII) following art-known N-alkylationprocedures with an alkylating reagent of formula (XIII), wherein W³ isan appropriate leaving group, e.g. halo. ##STR12##

Pure stereochemically isomeric forms of the compounds and theintermediates of this invention may be obtained by the application ofart-known procedures. Diastereoisomers may be separated by physicalseparation methods such as selective crystallization and chromatographictechniques, e.g. liquid chromatography. Enantiomers may be separatedfrom each other by the selective crystallization of their diastereomericsalts with optically active acids. Alternatively, enantiomers may beseparated by chromatographic techniques using chiral stationary phases.Said pure stereochemically isomeric forms may also be derived from thecorresponding pure stereochemically isomeric forms of the appropriatestarting materials, provided that the reaction occursstereospecifically. Preferably if a specific stereoisomer is desired,said compound will be synthesized by stereospecific methods ofpreparation. These methods will advantageously employ enantiomericallypure starting materials. Stereochemically isomeric forms of thecompounds of formula (I) are obviously intended to be included withinthe scope of the invention.

The compounds of formula (I), the pharmaceutically acceptable acid orbase addition salts and the stereochemically isomeric forms thereof areuseful agents for combating fungi and bacteria in vivo. Moreover thecompounds of formula (I) are soluble in aqueous solutions, which makesthen suitable for intravenous administration. Said compounds are foundto be active against a wide variety of fungi, such as Candida albicans,Aspergillus fumigatus, Cryptococcus neoformans, Coccidioides immitis,Histoplasma capsulatum, Blastomyces dermatitidis, Sporothrix schenkii,Fonsecaea sp., Microsporum canis, Paracoccidioides immitis, Trichophytonsp, Cladosporium carrionii, and against bacteria such as, for example,Erysipelotrix insidiosa, Staphylococci such as Staphylococcushaemolyticus and Streptococci such as Streptococcus pyogenes.

The intermediates of formula (II), the pharmaceutically acceptable acidaddition salts thereof and the stereochemically isomeric forms thereofare also useful in treating or preventing diseases associated withfungal infections and thus form a further aspect of the presentinvention. An interesting group of compounds of formula (II) are cis-4-4- 4- 4-2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl!-methoxy!-phenyl!-1-piperazinyl!phenyl!-2,4-dihydro-2-(2-hydroxy-3,3-dimethylbutyl)-3H-1,2,4-triazol-3-one,the pharmaceutically acceptable acid addition salts and thestereochemically isomeric forms thereof.

The present invention also provides compositions for treating orpreventing fungal infections comprising an antifungally effective amountof a compound of formula (I) or an intermediate of formula (II) and apharmaceutically acceptable carrier or diluent.

In view of their useful pharmacological properties, the subjectcompounds may be formulated into various pharmaceutical forms foradministration purposes. To prepare the pharmaceutical compositions ofthis invention, an effective amount of a particular compound, in base oracid addition salt form, as the active ingredient is combined inintimate admixture with a pharmaceutically acceptable carrier, whichcarrier may take a wide variety of forms depending on the form ofpreparation desired for administration. These pharmaceuticalcompositions are desirably in unitary dosage form suitable, preferably,for administration orally, rectally, percutaneously, or by parenteralinjection. For example, in preparing the compositions in oral dosageform, any of the usual pharmaceutical media may be employed, such as,for example, water, glycols, oils, alcohols and the like in the case oforal liquid preparations such as suspensions, syrups, elixirs andsolutions: or solid carders such as starches, sugars, kaolin,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules and tablets. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. For parenteral compositions, the carrier willusually comprise sterile water, at least in large part, though otheringredients, to aid solubility for example, e.g. cyclodextrins, may beincluded. Injectable solutions, for example, may be prepared in whichthe carrier comprises saline solution, glucose solution or a mixture ofsaline and glucose solution. Injectable suspensions may also be preparedin which case appropriate liquid carriers, suspending agents and thelike may be employed. In the compositions suitable for percutaneousadministration, the carrier optionally comprises a penetration enhancingagent and/or a suitable wetting agent, optionally combined with suitableadditives of any nature in minor proportions, which additives do notcause a significant deleterious effect to the skin. Said additives mayfacilitate the administration to the skin and/or may be helpful forpreparing the desired compositions. These compositions may beadministered in various ways, e.g., as a transdermal patch, as aspot-on, as an ointment. It is especially advantageous to formulate theaforementioned pharmaceutical compositions in dosage unit form for easeof administration and uniformity of dosage. Dosage unit form as used inthe specification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,injectable solutions or suspensions, teaspoonfuls, tablespoonfuls andthe like, and segregated multiples thereof.

Appropriate cyclodextrin derivatives are α-, β-, γ-cyclodextrins orethers and mixed ethers thereof wherein one or more of the hydroxygroups of the anhydroglucose units of the cyclodextrin are substitutedwith C₁₋₆ alkyl, particularly methyl, ethyl or isopropyl; hydroxyC₁₋₆alkyl, particularly hydroxyethyl, hydroxypropyl or hydroxy-butyl;carboxyC₁₋₆ alkyl, particularly carboxymethyl or carboxyethyl; C₁₋₆alkyl-carbonyl, particularly acetyl; C₁₋₆ alkyloxycarbonylC₁₋₆ alkyl orcarboxyC₁₋₆ alkyl-oxyC₁₋₆ alkyl, particularly carboxymethoxypropyl orcarboxyethoxypropyl; C₁₋₆ alkylcarbonyloxyC₁₋₆ alkyl, particularly2-acetyloxypropyl. Especially noteworthy as complexants and/orsolubilizers are β-CD, 2,6-dimethyl-β-CD, 2-hydroxyethyl-β-CD,2-hydroxyethyl-γ-CD, 2-hydroxypropyl-γ-CD and(2-carboxymethoxy)propyl-β-CD, and in particular 2-hydroxypropyl-β-CD.

The term mixed ether denotes cyclodextrin derivatives wherein at leasttwo cyclodextrin hydroxy groups are etherified with different groupssuch as, for example, hydroxypropyl and hydroxyethyl.

Those of skill in treating warm-blooded animals suffering from diseasescaused by fungi and/or bacteria could easily determine the effectiveamount from the test results given herein. In general, it iscontemplated that an effective amount would be from 0.01 mg/kg to 50mg/kg body weight, and more preferably from 0.05 mg/kg to 20 mg/kg bodyweight.

EXPERIMENTAL PART

Of some compounds of formula (I), the absolute stereochemicalconfiguration was not experimentally determined. In those cases thestereochemically isomeric form which was first isolated is designated as"A" and the second as "B".

A. Preparation of the Intermediates Example 1

To a stirred and cooled (ice-bath) mixture of2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-1,2-propanediol (30 g),methanesulfonic acid (50 ml) and dichloromethane (500 ml) was addeddropwise 1-bromo-2,2-diethoxyethane (17 ml). After stirring for 3 hoursat 0° C., the reaction mixture was poured into sodium hydrogen carbonate(aq.). The product was extracted with dichloromethane and the extractwas dried, filtered and evaporated. The residue was purified twice bycolumn chromatography (silica gel; CHCl₃ /CH₃ OH 99:1; CHCl₃ /CH₃OH/hexane/CH₃ COOC₂ H₅ 49:1:20:30). The eluent of the desired fractionwas evaporated, yielding 8 g (19.0% ) of cis-1-2-(bromomethyl)-4-(2,4-difluorophenyl)-1,3-dioxolan-4-yl!methyl!-1H-1,2,4-triazole;mp. 76.3° C. (interm. 1).

Example 2

A mixture of 2-(3,3-dimethyl-2-oxobutyl)-2,4-dihydro-4- 4-4-(4-hydroxyphenyl)-1-piperazinyl!phenyl!-3H-1,2,4-triazol-3-one (0.01mol) and sodium hydride (0.012 mol) in N,N-dimethylformamide (100 ml)was stirred under nitrogen at 70° C. Intermediate (1) (0.012 mol) wasadded and the mixture was stirred further overnight. Intermediate (1) (2g) was added again and the mixture was stirred at 70° C. for 6 hours andthen at room temperature overnight. The mixture was evaporated, theresidue was taken up in dichloromethane and washed. The organic layerwas dried, filtered off and evaporated. The residue was purified bycolumn chromatography over silica gel (eluent: CH₂ Cl₂ /hexane/ethylacetate 50/20/30). The pure fractions were collected and evaporated. Theresidue was purified further on a glass filter over silica gel/NH₂(eluent: CH₂ Cl₂). The pure fractions were collected and evaporated. Theresidue was crystallized from ethyl acetate, yielding 2.2 g (31%) of(±)-cis-4- 4- 4- 4-4-(2,4-difluorophenyl)-4-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-2-yl!methoxy!phenyl!-1-piperazinyl!phenyl!-2-(3,3-dimethyl-2-oxobutyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;197.1° C. (interm. 2).

Example 3

a) A mixture ofcis-2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolane-4-methanol(0.2 mol) in pyridine (400 ml) and dichloromethane (250 ml) was stirredat room temperature. A solution of 4-cyanobenzoyl chloride (0.22 mol) indichloromethane (150 ml) was added dropwise. The reaction mixture wasstirred for 24 hours at room temperature. The reaction mixture wasdiluted with water. The organic layer was separated, dried (MgSO₄),filtered and the solvent was evaporated. The residue was crystallizedfrom methylbenzene. The crystals were filtered off and dried. Thisfraction was purified by column chromatography over a Chiracell ODcolumn (eluent: C₂ H₅ OH). The first peak fractions were combined andthe solvent was evaporated. The residue was crystallized from4-methyl-2-pentanone. The crystals were filtered off and dried, yielding21.2 g (24.9%) of (+)-cis-2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl!methyl4-cyanobenzoate; mp. 146.3° C.; α!_(D) ²⁰ =+22.71° (c=0.5% in methanol)(interm. 3). The second peak fractions were combined and the solvent wasevaporated. The residue was crystallized from 4-methyl-2-pentanone. Thecrystals were filtered off and dried, yielding 21.4 g (25.1%) (-)-cis-2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl!-methyl4-cyanobenzoate; mp. 144.0° C.; α!_(D) ²⁰ =-22.64° (c=0.5% in methanol)(interm. 4).

b) A mixture of intermediate (3) (0.049 mol) and sodium hydroxide 50%(0.059 mol) in water (300 ml) and 1,4-dioxane (300 ml) was stirred for24 hours at room temperature. The solvent was evaporated. The residuewas partitioned between water and dichloromethane. The organic layer wasseparated, dried (MgSO₄), filtered and the solvent was evaporated. Theresidue was crystallized from 4-methyl-2-pentanone. The crystals werefiltered off and dried, yielding 10.1 g (70%) of(+)-cis-2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolane-4-methanol;mp. 123.0° C.; α!_(D) ²⁰ =+16.58° (c=0.5% in methanol) (interm. 5)

In a similar manner was also prepared:(-)-cis-2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolane-4-methanol;mp. 123.2° C.; α!_(D) ²⁰ =-15.97° (c=0.5% in methanol) (interm. 6).

c) A mixture of intermediate (5) (0.02 mol) and N,N-diethylethanamine(0.03 mol) in dichloromethane (50 ml) was stirred at room temperature.Methanesulfonyl chloride (0.03 mol) was added dropwise and the reactionmixture was stirred overnight at room temperature. The solvent wasevaporated. The residue was partitioned between methylbenzene and water.A precipitate was formed, which was filtered off, dried andrecrystallized from 2,2'-oxybispropane/4-methyl-2-pentanone. Theprecipitate was filtered off and dried (vacuum; 40° C.), yielding twofractions. Those fractions were combined and recrystallized from2,2'-oxybispropane/4-methyl-2-pentanone. The precipitate was filteredoff and dried (vacuum; 40° C.), yielding 5.88 g (78.3%) of(+)-cis-2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolane-4-methanolmethanesulfonate(ester); α!_(D) ²⁰ =+15.50° (c=0.2% in methanol)(interm. 7).

In a similar manner was also prepared:(-)-cis-2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolane-4-methanolmethanesulfonate (ester); α!_(D) ²⁰ =-14.50° (c=0.2% in methanol)(interm. 8).

Example 4

a) A mixture of 2,4-dihydro-2-(2-hydroxy-3,3-dimethylbutyl)-4- 4-4-(4-hydroxyphenyl)-1-piperazinyl!phenyl!-3H-1,2,4-triazol-3-one (0.046mol), 2-(chlorodimethylsilyl)-2-methylpropane (0.063 mol) and1H-imidazole (0.19 mol) in N,N-dimethylformamide (300 ml) was stirredfor 4 hours at 50° C. The reaction mixture was poured out into water.The resulting precipitate was filtered off and dried, yielding 21 g(83%) of product. A sample (1 g) was triturated in 2,2'-oxybispropane,filtered off and dried, yielding 0.7 g of (±)-4- 4- 4- 4-(1,1-dimethylethyl)dimethylsilyl!oxy!phenyl!-1-piperazinyl!phenyl!-2-(2-hydroxy-3,3-dimethylbutyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;mp. 196.1° C. (interm. 9).

b) Intermediate (9) (0.036 mol, mixture of enantiomers) was separated init's enantiomers by column chromatography over a Chiracell® OD column(eluent: n-hexanes/2-propanol 65/35). The fraction, corresponding to afirst chromatographic peak, was collected and the solvent wasevaporated. The residue was crystallized from acetonitrile. Theprecipitate was filtered off and dried (vacuum; 50° C.); yielding 1.56 g(7.8%) of (-)-4- 4- 4- 4-(1,1-dimethylethyl)dimethylsilyl!oxy!phenyl!-1-piperazinyl!phenyl!-2-(2-hydroxy-3,3-dimethylbutyl)-2,4-dihydro-3H-1,2,4-triazol-3-one(interm. 10). The fraction, corresponding to a second chromatographicpeak, was collected and the solvent was evaporated. The residue wascrystallized from acetonitrile. The precipitate was filtered off anddried (vacuum; 50° C.); yielding 2.28 g (11.4%) of (+)-4- 4- 4- 4-(1,1-dimethylethyl)dimethylsilyl!oxy!phenyl!-1-piperazinyl!phenyl!-2-(2-hydroxy-3,3-dimethylbutyl)-2,4-dihydro-3H-1,2,4-triazol-3-one(interm. 11).

c) A mixture of intermediate (10) (0.0135 mol) in dichloromethane (150ml) was stirred until complete dissolution. A solution oftetrabutylammonium fluoride in tetrahydrofuran (0.015 mol) was added inone portion and the reaction mixture was stirred for 1 hour at roomtemperature. The mixture was diluted with water (150 ml) and stirred for1 hour. The precipitate was filtered off and recrystallized from2-methoxyethanol. The product was filtered off and dried (vacuum; 60°C.), yielding 4.7 g (79.6%) of(-)-2,4-dihydro-2-(2-hydroxy-3,3-dimethylbutyl)-4- 4-4-(4-hydroxyphenyl)-1-piperazinyl!phenyl!-3H-1,2,4-triazol-3-one; α!_(D)²⁰ =-3.14° (c=0.1% in N,N-dimethylformamide) (interm. 12).

In a similar manner was also prepared:(+)-2,4-dihydro-2-(2-hydroxy-3,3-dimethylbutyl)-4- 4-4-(4-hydroxyphenyl)-1-piperazinyl!phenyl!-3H-1,2,4-triazol-3-one; α!_(D)²⁰ =+6.22° (c=0.1% in N,N-dimethylformamide) (interm. 13).

Example 5

A mixture of cis-4- 4- 4- 4-2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl!-methoxy!phenyl!-1-piperazinyl!phenyl!-2,4-dihydro-3H-1,2,4-triazol-3-one(9.3 g), 1-bromo-3,3-dimethyl-2-butanone (2.8 g), sodium carbonate (6.4g) and 1,3-dimethyl-2-imidazolidinone (52.2 g) was stirred for 5 hoursat 100° C. After cooling, the reaction mixture was poured into water.The formed precipitation was filtered off and dissolved indichloromethane. This solution was dried, filtered and evaporated. Theresidue was purified by column chromatography (silica gel; CH₂ Cl₂ /CH₃OH 98:2). The eluent of the desired fraction was evaporated and theresidue was crystallized from 4-methyl-2-pentanone. The product wasfiltered off and dried, yielding 5.5 g (51.3%) of cis-4- 4- 4- 4-2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl-methyl)-1,3-dioxolan-4-yl!-methoxy!phenyl!-1-piperazinyl!phenyl!-2-(3,3-dimethyl-2-oxobutyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;mp. 176.2° C. (interm. 14).

Example 6

To a mixture of intermediate (14) (4.5 g), 1,4-dioxane (40 ml) andmethanol (3 ml) was added dropwise a solution of sodium tetrahydroborate(0.3 g) in some water. After stirring overnight, the reaction mixturewas poured into water and acidified with acetic acid to ±pH 5. Theprecipitate was filtered off, washed with water, dried and purified bycolumn chromatography (silica gel; CH₂ Cl₂ /CH₃ OH 98:2). The eluent ofthe desired fraction was evaporated and the residue was crystallizedfrom 2-propanol, yielding 2.2 g (48.7%) of cis-4- 4- 4- 4-2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl!-methoxy!phenyl!-1-piperazinyl!phenyl!-2,4-dihydro-2-(2-hydroxy-3,3-dimethylbutyl)-3H-1,2,4-triazol-3-one;mp. 196.4° C. (interm. 15).

Example 7

Sodium hydride (0.00675 mol) was added portionwise to a mixture ofintermediate (12) (0.00595 mol) in N,N-dimethylformamide (50 ml),stirred at room temperature. The mixture was stirred for 90 minutes atroom temperature. Intermediate (7) (0.0054 mol) was added and thereaction mixture was stirred for 4 hours at 60° C. The mixture wascooled and the solvent was evaporated. The residue was partitionedbetween dichloromethane and water. The organic layer was separated,dried, filtered and the solvent was evaporated. The residue was purifiedby column chromatography over an aminopropyl column (eluent: CH₂ Cl₂/CH₃ OH 96/4). The pure fractions were collected and the solvent wasevaporated. The residue was crystallized from 4-methyl-2-pentanone. Theprecipitate was filtered off and dried (vacuum; 50° C.), yielding 1.67 g(43.1%) of (+)- cis(+)(B)!-4- 4- 4- 4-2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl!methoxy!phenyl!-1-piperazinyl!phenyl!-2,4-dihydro-2-(2-hydroxy-3,3-dimethylbutyl)-3H-1,2,4-triazol-3-one;mp. 191.9° C.; α!_(D) ²⁰ =+12.03° (c=0.5% in dichloromethane)(interm.20).

                                      TABLE 1                                     __________________________________________________________________________     ##STR13##                                                                    Int. No.                                                                             Ex. No.   R    R.sup.1                                                                            R.sup.2                                                                            Physical data                                 __________________________________________________________________________    15     6         H    F    F    mp. 196.4° C./cis                      16     6         H    Cl   Cl   mp. 187.1° C./cis                      17     6         H    Cl   H    mp. 201.5° C./cis                      18     6         H    F    H    mp. 213.2° C./cis                      19     6         H    F    H    mp. 211.1° C./trans                    20     7         H    F    F    mp. 191.9° C./ α!.sub.D.sup.2                                    0 = +12.03°                                                            (c = 0.5% in dichloromethane)/                                                (+)- cis(+)(B)!                               21     7         H    F    F    mp. 213.2° C./ α!.sub.D.sup.2                                    0 = -7.89°                                                             (c = 0.5% in dichloromethane)                                                 (-)- cis(-)(B)!                               22     7         H    F    F    mp. 212.5° C./ α!.sub.D.sup.2                                    0 = +8.38°                                                             (c = 0.5% in dichloromethane)                                                 (+)- cis(+)(A)!                               23     7         H    F    F    mp. 185.6° C./ α!.sub.D.sup.2                                    0 = -5.08°                                                             (c = 0.5% in N,N-dimethylformamide)                                           (-)- cis(-)(A)!                               __________________________________________________________________________

Example 8

A mixture of intermediate (2) (0.0025 mol) in dichloromethane (100 ml)and methanol (100 ml) was stirred at room temperature. Sodiumborohydride (0.005 mol) was added and the mixture was stirred for 4hours. Water (100 ml) was added, the mixture was stirred overnight andseparated. The organic layer was washed, dried, filtered off andevaporated. The residue was crystallized from ethyl acetate, yielding1.6 g (89.3%) of (±)-cis-4- 4- 4- 4-4-(2,4-difluorophenyl)-4-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-2-yl!methoxy!phenyl!-1-piperazinyl!phenyl!-2,4-dihydro-2-(2-hydroxy-3,3-dimethylbutyl)-3H-1,2,4-triazol-3-one;mp. 184.1° C. (interm. 24).

Example 9

A mixture of 2,4-dihydro-2-(2-hydroxy-3,3-dimethylbutyl)-4- 4-4-(4-hydroxyphenyl)-1-piperazinyl!phenyl!-3H-1,2,4-triazol-3-one (0.0035mol), cis-5-(2,4-difluorophenyl)tetrahydro-5-(1H-1,2,4-triazol-1-ylmethyl)-3-furanmethanol4-methylbenzenesulfonate (the preparation of which is described inEuropean Patent Application 0,539,938) (0.0033 mol) and sodium hydroxide(0.01 mol) in N,N-dimethylformamide (50 ml) was stirred under nitrogenat 50° C. for 4 hours and the mixture was stirred further under nitrogenat 60° C. for 2 hours. The mixture was cooled and water was added. Theproduct was crystallized out, filtered off and dried. The residue waspurified on a glass filter over silica gel (eluent: CH₂ Cl₂ /CH₃ OH99/1). The pure fractions were collected and evaporated. The residue wasrecrystallized from dioxane/2,2'-oxybispropane, yielding 1.7 g (72%) of(±)-cis-4- 4- 4- 4-5-(2,4-difluorophenyl)tetrahydro-5-(1H-1,2,4-triazol-1-ylmethyl)-3-furanyl!methoxy!phenyl!-1-piperazinyl!phenyl!-2,4-dihydro-2-(2-hydroxy-3,3-dimethylbutyl)-3H-1,2,4-triazol-3-one;mp. 210.8° C. (interm. 25).

Example 10

Chloroacetyl chloride (0.02 mol) was added to a stirring mixture ofintermediate (15) (0.0082 mol) in dichloromethane (100 ml). Pyridine(0.037 mol) was added dropwise and the mixture was stirred for 2 hours.Hydrochloric acid 1N (50 ml) was added, the mixture was stirred for 2hours and separated. The organic layer was washed with a sodium hydrogencarbonate-solution, dried, filtered off and evaporated. The residue wascrystallized and triturated in 4-methyl-2-pentanone/2,2'-oxybispropane,yielding 6.3 g (96.8%) of product. A sample (1 g) was recrystallizedfrom 4-methyl-2-pentanone, yielding 0.6 g of (±)-cis-1- 4- 4- 4- 4-2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl!methoxy!phenyl!-1-piperazinyl!phenyl!-4,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl!methyl!-2,2-dimethylpropylchloroacetate (interm. 26).

Example 11

A mixture of (±)-2,4-dihydro-4-(2-hydroxy-3,3-dimethylbutyl)-2- 4-4-(4-hydroxyphenyl)-1-piperazinyl!phenyl!-3H-1,2,4-triazol-3-one (0.0068mol),(±)-cis-2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolane-4-methanolmethanesulfonate (ester) (0.0082 mol) and sodium hydroxide (0.025 mol)in N,N-dimethylformamide (100 ml) was stirred under nitrogen at 60° C.for 4 hours. The mixture was cooled, water was added and the mixture wasstirred. The precipitate was filtered off and dried. The residue waspurified on a glass filter over silica gel (eluent: CH₂ Cl₂ /CH₃OH/ethyl acetate/n-hexane 48/2/30/20). The pure fractions were collectedand evaporated. The residue was recrystallized from4-methyl-2-pentanone, yielding 1.1 g (22%) of (±)-cis-2- 4- 4- 4-2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl!methoxy!phenyl!-1-piperazinyl!phenyl!-2,4-dihydro-4-(2-hydroxy-3,3-dimethyl-butyl)-3H-1,2,4-triazol-3-one;mp. 201.2° C. (interm. 27).

Example 12

A mixture of (±)-cis-1- 4- 4- 4-2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl-methyl)-1,3-dioxolan-4-yl!methoxy!phenyl!-1-piperazinyl!phenyl!-3-(3,3-dimethyl-2-oxobutyl)-1,3-dihydro-2H-imidazol-2-one(0.0036 mol) in methanol (50 ml) and dichloromethane (50 ml) wasstirred. Sodium borohydride (0.01 mol) was added and the mixture wasstirred at room temperature for 1 hour. Water (100 ml) was added and themixture was stirred for 1 hour. The mixture was separated and theaqueous layer was extracted with dichloromethane. The organic layer wasdried, filtered off and evaporated. The residue was purified on a glassfilter over silica gel (eluent: CH₂ Cl₂ /CH₃ OH 99/1). The purefractions were collected and evaporated. The residue was recrystallizedfrom 4-methyl-2-pentanone, yielding 1.9 g (73%) of (±)-cis-1- 4- 4- 4-2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl!methoxy!phenyl!-1-piperazinyl!phenyl!-3-(2-hydroxy-3,3-dimethylbutyl)-2-imidazolidinone;mp. 196.8° C. (interm. 29).

                                      TABLE 2                                     __________________________________________________________________________     ##STR14##                                                                    Interm. No.                                                                           Ex. No. AB            Physical data                                   __________________________________________________________________________    27      11      NCH           mp. 201.2° C.                            28      11      (CO)C(CH.sub.3).sub.2                                                                       mp. 141.8° C.                            29      12      CH.sub.2CH.sub.2                                                                            mp. 196.8° C.                            30      11      CHN           mp. 147.6° C./(+)- (B-cis),B!/ .alpha                                  .!.sub.D.sup.20 = +1.20°                                               (c = 0.5% in methanol)/                         __________________________________________________________________________

B. Preparation of the Final Compounds Example 13

A mixture of intermediate (15) (0.0014 mol), diphenyl chlorophosphate(0.003 mol) and N,N-dimethyl-4-pyridinamine (1 g) in dichloromethane (30ml) was stirred at room temperature for 2 hours. The mixture waspurified on a glass filter over silica gel (eluent: CH₂ Cl₂ /CH₃ OH98/2). The pure fractions were collected and evaporated. The residue wasrecrystallized from 4-methyl-2-pentanone/2,2'-oxybispropane, yielding1.1 g (83%) (±)-cis-1- 4- 4- 4- 4-2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl!methoxy!phenyl!-1-piperazinyl!phenyl!-4,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl!methyl!-2,2-dimethylpropyldiphenyl phosphate; mp. 170.8° C. (comp. 1).

Example 14

A mixture of compound (1) (0.0029 mol) and a dispersion of sodiumhydroxide 50% solution (5 g) in 1,4-dioxane (50 ml) was stirred at roomtemperature for 6 hours. Water (200 ml) was added, the mixture wasfiltered over dicalite and the filtrate was acidified with hydrochloricacid till pH=2-3. The mixture was extracted three times withdichloromethane. The combined organic layers were dried, filtered offand evaporated. The residue was dissolved in a saturated sodium hydrogencarbonate solution (100 ml), washed with 2,2'-oxybispropane andextracted twice with dichloromethane (500 ml) and methanol (100 ml). Thecombined organic layers were dried, filtered off and evaporated. Theresidue was crystallized from 2-propanol and a little water, yielding1.2 g (46%) of (±)-cis-1- 4- 4- 4- 4-2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl!methoxy!phenyl!-1-piperazinyl!phenyl!-4,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl!methyl!-2,2-dimethylpropylphenyl sodium phosphate; mp. 167.0° C. (comp. 2).

Example 15

A mixture of compound (1) (0.0038 mol) and sodium hydroxide 50% solution(5 g) in 1,4-dioxane (100 ml) was stirred at room temperature overnight.Water (600 ml) was added, the mixture was filtered over dicalite and thefiltrate was acidified with hydrochloric acid. The precipitate wasfiltered off (*) and the filtrate was extracted with dichloromethane.The mixture was evaporated. The residue, the precipitate (*) and sodiumhydroxide 50% (5 g) were stirred at 60° C. for 24 hours. Sodiumhydroxide 50% (3 g) was added again and the mixture was stirred at 60°C. for 48 hours. The mixture was cooled, acidified with hydrochloricacid 1N till pH=4 and extracted with dichloromethane. The combinedorganic layers were dried, filtered off and evaporated. The residue wasboiled up in methanol (70 ml), filtered off and methanol/ammonia (20 ml)was added to the filtrate. The mixture was boiled up in 2-propanol (20ml) and cooled. The mixture was filtered off, the precipitate wasdissolved in water (200 ml) and washed twice with ethyl acetate. Theaqueous layer was acidified with hydrochloric acid 1N and extractedthree times with dichloromethane. The combined organic layers weredried, filtered off and evaporated. The residue was dissolved inmethanol (70 ml) and methanol/ammonia (10 ml) was added. The precipitatewas filtered off and dried, yielding 1.6 g (51%) of (±)-ammonium cis-1-4- 4- 4- 4-2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl!methoxy!phenyl!-1-piperazinyl!phenyl!-4,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl!methyl!-2,2-dimethylpropylphosphate; mp. 189.6° C. (comp. 3).

Example 16

Sodium hydroxide 50% (1.4 mol) was added to a suspension of (±)-cis-1-4- 4- 4- 4-2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl!methoxy!phenyl!-1-piperazinyl!phenyl!-4,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl!methyl!-2,2-dimethylpropyldiphenyl phosphate (0.07 mol) in 1,4-dioxane (1400 ml) under N₂ flow. .The resulting suspension was heated to 60° C. The reaction solution wasstirred for 92 hours at 60° C. The mixture was allowed to cool to 25° C.The mixture was poured out into distilled water (5.25 liter) and thismixture was stirred vigorously for 1 hour. The mixture was filtered. Thefiltrate was acidified (pH=2.7) with hydrochloric acid and recipitationresulted. The aqueous layer was extracted with CH₂ Cl₂ (1×2 liter; 1×1.5liter). The combined extracts were dried (Na₂ SO₄), filtered and thesolvent was evaporated. The residue (71.02 g; 124.7% yield) was stirredin 2-propanol (1050 ml), heated to reflux temperature, stirred andrefluxed for 5 min, cooled on an ice bath while stirring vigorously,cooled to 20° C. and stirring was continued overnight. The precipitatewas filtered off, washed with 2-propanol (1×35 ml), diisopropylether(2×35 ml) and dried (vacuum; 50° C.), yielding 48.10 g of (±)-cis-4- 4-4- 4-2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl!methoxy!phenyl!-1-piperazinyl!phenyl!-2-3,3-dimethyl-2-(phosphonooxy)butyl!-2,4-dihydro-3H-1,2,4-triazol-3-onehemihydrate; mp. 156.2° C. (comp. 17).

Example 17

1-Deoxy-1-(methylamino)-D-glucitol (0.02 mol) was added to a mixture ofcompound (17) (0.005 mol) in water (70 ml) and the mixture was stirreduntil complete dissolution (30 min). The solvent was evaporated. Toluenewas added and azeotroped on the rotary evaporator. Ethanol (250 ml) wasadded and the mixture was stirred vigorously. The mixture was cooled onan ice bath and stirred for 1 hour and precipitation resulted. Themixture was allowed to warm to room temperature (20° C.). The mixturewas stirred for 18 hours at room temperature and the resultingprecipitate was filtered off, washed with ethanol, with diisopropylether(2×10 ml) and dried (vacuum; 50° C.), yielding: 6.14 g (1). The filtratewas evaporated. The residue was dried (vacuum; 50° C.), yielding: 1.98 g(2). Fraction (1) was ground, stirred vigorously for 5 hours in ethanol(200 ml) and the resulting precipitate was filtered off, washed withethanol (4×5 ml) and dried (vacuum; 45°-50° C.; 64 hours), yielding:4.98 g (±)-cis-4- 4- 4- 4-2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl!methoxy!phenyl!-1-piperazinyl!phenyl!-2-3,3-dimethyl-2-(phosphonooxy)butyl!-2,4-dihydro-3H-1,2,4-triazol-3-one1-deoxy-1-(methylamine)-D-glucitol (1:2).monohydrate (comp. 18)

Example 18

A mixture of intermediate (26) (0.0025 mol) and pyrrolidine (0.014 mol)in N,N-dimethylformamide (50 ml) was stirred at room temperature for 4hours. Water was added and the mixture was stirred. The precipitate wasfiltered off, washed with water and purified on a glass filter oversilica gel (eluent 1: CH₂ Cl₂ /CH₃ OH 98/2 and eluent 2: CH₂ Cl₂ /CH₃ OH95/5). The suitable fractions were collected and evaporated. The residuewas dissolved in dichloromethane (100 ml) and stirred with hydrochloricacid 0.4N (50 ml). The mixture was separated and the aqueous layer wasextracted four times with dichloromethane. The combined organic layerswere dried, filtered off and evaporated. The oily residue was dissolvedin dichloromethane, washed with a sodium hydrogen carbonate solution,dried, filtered off and evaporated. The residue was crystallized from4-methyl-2-pentanone, yielding 1.1 g (53% ) of (±)-cis-1- 4- 4- 4- 4-2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl!methoxy!phenyl!-1-piperazinyl!phenyl!-4,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl!methyl!-2,2-dimethylpropyl1-pyrrolidineacetate; mp. 156.7° C. (comp. 28).

Example 19

A mixture of intermediate (16) (0.0066 mol), 4-methyl-1-piperazineaceticacid dihydrochloride (0.013 mol), 1,3-dicyclohexylcarbodiimide (0.026mol) and N,N-dimethyl-4-pyridinamine 0.026 mol) in dichloromethane (100ml) was stirred at room temperature for 4 hours. Hydrochloric acid 1N(200 ml) was added and the mixture was stirred for 1 hour. Theprecipitate was filtered off, water (600 ml) was added and the mixturewas separated (*). The aqueous layer was washed with dichloromethane(100 ml) and separated. The aqueous layer was neutralized with pyridineand extracted five times with dichloromethane. The combined organiclayers were dried, filtered off and evaporated, yielding 4.5 g offraction 1. (*) The organic layer was washed with hydrochloric acid 1N(100 ml) and separated. The aqueous layer was neutralized with pyridineand extracted twice with dichloromethane. The combined organic layerswere dried, filtered off and evaporated, yielding 2 g of fraction 2.Fractions 1 and 2 were put together and recrystallized from(acetonitrile 2% water)/2,2'oxybispropane, yielding 3.8 g (61%) of(±)-cis-1- 4- 4- 4- 4-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl!methoxy!phenyl!-1-piperazinyl!phenyl!-4,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl!methyl!-2,2-dimethylpropyl4-methyl-1-piperazineacetate . monohydrochloride . hemihydrate; mp.156.0° C. (comp. 32).

Example 20

A mixture of compound (17) (0.0034 mol) in a solution of hydrochloricacid in 2-propanol (10 ml) and dichloromethane (60 ml) was stirred andrefluxed for 30 minutes. The mixture was evaporated. The residue wasdissolved in water and filtered off. The filtrate was neutralized with asodium hydrogen carbonate solution and extracted with dichloromethane.The organic layer was dried, filtered off and evaporated. The residuewas dissolved in hydrochloric acid 0.5N (50 ml) and washed three timeswith ethyl acetate (100 ml). The aqueous layer was neutralized withpyridine and extracted three times with dichloromethane. The combinedorganic layers were dried, filtered off and evaporated. The residue wascrystallized from acetonitrile and a little N,N-dimethylformamide,yielding 1.3 g (46%) of (±)-cis-1- 4- 4- 4- 4-2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl!methoxy!phenyl!-1-piperazinyl!phenyl!-4,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl!methyl!-2,2-dimethylpropylβ-alanine monohydrochloride; mp. 217.9° C. (comp. 36).

Example 21

A mixture of (±)-cis-N- 1- 3- 1- 4- 4- 4- 4-2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl!methoxy!phenyl!-1-piperazinyl!phenyl!-4,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl!methyl!-2,2-dimethylpropoxy!-3-oxopropyl!-1,4-dihydro-4-pyridinylidene!-N-methylmethanaminiumchloride monohydrate (0.0024 mol) and pyrrolidine (0.01 mol) inN,N-dimethylformamide (50 ml) was stirred at room temperature for 1hour. The mixture was poured into water and extracted three times withdichloromethane. The combined organic layers were washed with water,dried, filtered off and evaporated. The residue was dissolved inhydrochloric acid 0.5N (500 ml) and washed three times with ethylacetate (100 ml). The aqueous layer was neutralized with pyridine andextracted three times with dichloromethane. The combined organic layerswere dried, filtered off and evaporated. The residue was crystallizedfrom 4-methyl-2-pentanone and water (0.5 ml). The residue was purifiedon a glass filter over silica gel (eluent: CH₂ Cl₂ /CH₃ OH 96/4). Thesuitable fractions were collected and evaporated. The residue wasdissolved in hydrochloric acid 1N (50 ml), neutralized with pyridine andextracted five times with dichloromethane. The combined organic layerswere dried, filtered off and evaporated. The residue was crystallizedfrom 4-methyl-2-pentanone and water (5 drops), yielding 1.1 g (51%) of(±)-cis-1- 4- 4- 4- 4-2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl!methoxy!phenyl!-1-piperazinyl!phenyl!-4,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl!methyl!-2,2-dimethylpropyl1-pyrrolidinepropanoate . monohydrochloride . monohydrate; mp. 154.4° C.(comp. 37)

                                      TABLE 3                                     __________________________________________________________________________     ##STR15##                                                                    Co. No.                                                                             Ex. No. R   R.sup.1                                                                           R.sup.2                                                                           R.sup.3                                                                            R.sup.4                                                                            Physical data                             __________________________________________________________________________    1     13      H   F   F   C.sub.6 H.sub.5                                                                    C.sub.6 H.sub.5                                                                    mp. 170.8° C.                      2     14      H   F   F   H    C.sub.6 H.sub.5                                                                    mp. 167.0° C./Na.sup.+             3     15      H   F   F   H    H    mp. 189.6° C./NH.sub.4.sup.+       4     13      H   Cl  Cl  C.sub.6 H.sub.5                                                                    C.sub.6 H.sub.5                                                                    mp. 167.1° C.                      5     15      H   Cl  Cl  H    H    mp. 188.2° C./NH.sub.4.sup.+       6     13      H   Cl  H   C.sub.6 H.sub.5                                                                    C.sub.6 H.sub.5                                                                    mp. 174.2° C.                      7     15      H   Cl  H   H    H    mp. 195.5° C./NH.sub.4.sup.+       8     13      H   F   H   C.sub.6 H.sub.5                                                                    C.sub.6 H.sub.5                                                                    mp. 184.6° C.                      9     15      H   F   H   H    H    mp. 159.8° C./NH.sub.4.sup.+       10    13      H   F   F   C.sub.6 H.sub.5                                                                    C.sub.6 H.sub.5                                                                    mp. 147.6° C.                                                           α!.sub.D.sup.20                                                        = +1.20°                                                               (c = 0.5% in methanol)                                                        (+)- (B-cis),B!                           11    15      H   F   F   H    H    mp. 200.7° C./NH.sub.4.sup.+                                            α!.sub.D.sup.20                                                        = -15.8°                                                               (c = 0.1% in DMF)                                                             (+)- (B-cis),B!                           12    13      H   F   F   C.sub.6 H.sub.5                                                                    C.sub.6 H.sub.5                                                                    mp. 76.6° C.                                                            α!.sub.D.sup.20                                                        = -15.89°                                                              (c = 0.1% in methanol)                                                        (-)- (A-cis),B!                           13    13      H   F   F   C.sub.6 H.sub.5                                                                    C.sub.6 H.sub.5                                                                    mp. 76.7° C.                                                            α!.sub.D.sup.20                                                        = 13.62°                                                               (c = 0.1% in methanol)                                                        (-)- (B-cis),A!                           14    13      H   F   F   C.sub.6 H.sub.5                                                                    C.sub.6 H.sub.5                                                                    mp. 145.7° C.                                                           α!.sub.D.sup.20                                                        = -3.52°                                                               (c = 0.1% in methanol)                                                        (-)- (A-cis),A!                           15    13      H   F   F   C.sub.6 H.sub.5                                                                    C.sub.6 H.sub.5                                                                    cis                                       16    15      H   F   F   H    H    mp. 201.3° C./NH.sub.4.sup.+                                           cis                                       17    16      H   F   F   H    H    mp. 156.2° C.                                                          cis 1/2H.sub.2 O                          18    17      H   F   F   H    H    mp. 117.6° C.                                                          cis .2CH.sub.3NHCH.sub.2                                                      (COH).sub.4CH.sub.2OH                     19    17      H   F   F   H    H    mp. 184.7° C./cis                                                      C(CH.sub.2OH).sub.3 NH.sub.2              20    17      H   F   F   H    H    mp. 251.7° C./.2Na.sup.+                                               cis. 7/2H.sub.2 O                         21    15      H   F   F   H    H    mp. 202.7° C./NH.sub.4.sup.+                                           /                                                                              α!.sub.D.sup.20                                                        = 51.72°                                                               (c = 0.5% in DMF)/                                                            (-) (B-cis),A!                            22    15      H   F   F   H    H     (A-cis),A!                               23    16      H   F   F   H    H    mp. 171.6° C./                                                          α!.sub.D.sup.20                                                        = +10.93°                                                              (c = 0.5% in DMF)                         24    16      H   F   F   H    H     (B-cis),A!.H.sub.2 O                     25    16      H   F   F   H    H    NH.sub.4.sup.+ / (A-cis),B!               26    16      H   F   F   H    H    mp. 167.8° C./                                                          α!.sub.D.sup.20                                                        = +12.59°                                                              (c = 1% in DMF)                           27    15      H   F   F   H    H     α!.sub.D.sup.20                                                        = 3.70°                                                                (c = 0.5% in methanol)                    __________________________________________________________________________

                                      TABLE 4                                     __________________________________________________________________________     ##STR16##                                                                    Co. No.                                                                             Ex. No.                                                                              R   R.sup.1                                                                           R.sup.2                                                                           Alk                                                                                    ##STR17##      Physical                     __________________________________________________________________________                                                     data                         28    18     H   F   F   CH.sub.2                                                                               ##STR18##      mp. 156.7° C.         29    18     H   F   F   CH.sub.2                                                                               ##STR19##      mp. 155.3° C.         30    18     H   F   F   CH.sub.2                                                                               ##STR20##      mp. 166.3° C.         31    18     H   F   F   CH.sub.2                                                                               ##STR21##      mp. 171.7° C.                                                          .2HCl.H.sub.2 O              32    19     H   Cl  Cl  CH.sub.2                                                                               ##STR22##      mp. 156.0° C.                                                          .2HCl.1/2H.sub.2 O           33    19     H   F   F   CH.sub.2CH.sub.2                                                                       ##STR23##      mp. 213.7° C.                                                          .HCl                         34    19     H   F   F   CH.sub.2                                                                               ##STR24##      mp. 201.5° C.                                                          .HCl                         35    19     H   F   F   CH.sub.2CH.sub.2                                                                       ##STR25##      --                           36    20     H   F   F   CH.sub.2CH.sub.2                                                                      NH.sub.2        mp. 217.9° C.                                                          .HCl                         37    21     H   F   F   CH.sub.2CH.sub.2                                                                       ##STR26##      mp. 154.4° C.                                                          .HCl.H.sub.2 O               38    21     H   F   F   CH.sub.2                                                                              NH.sub.2        mp. 219.5° C.                                                          .HCl                         39    21     H   F   F   CH.sub.2CH.sub.2                                                                       ##STR27##      mp. 208.5° C.                                                          .2HCl                        __________________________________________________________________________

C. Physicochemical Example Example 22 Solubility

An excess of compound was added to 5 ml of solvent (the type of solventis specified in the table). The mixture was shaken during 1 hour at roomtemperature. The precipitate was filtered off. The pH of the remainingsolvent was measured and is shown in the table. The concentration of thecompound was measured via UV-spectroscopy and is shown in the column"Solubility".

    ______________________________________                                        Co. No. Solvent      pH     Solubility (mg/ml)                                ______________________________________                                        2       water        7.01   >6                                                3       water        6.95   31.93                                             7       water        6.80   0.35                                              9       water        6.65   2.65                                              29      0.1N HCl     1.62   4.89                                              30      0.1N HCl     1.65   5.22                                              33      0.1N HCl     1.65   >6                                                34      0.1N HCl     1.75   >6                                                36      0.1N HCl     1.25   >6                                                37      0.1N HCl     1.26   >6                                                38      0.1N HCl     1.59   >6                                                31      0.1N HCl     1.53   >6                                                ______________________________________                                    

D. Pharmacological Examples Example 23 Mouse Triple Mycosis Model

The test compounds were evaluated for their activity in a mouse model offungal infection in which three mycoses--vaginal candidosis, cutaneoustrichophytosis and disseminated aspergillosis--were establishedsimultaneously. The mice, in groups of 10, were pretreated withsubcutaneous injections of oestradiol valerate (500 μg) then inoculatedon day 0 with the following: 100 000 colony forming units (CFU)/g ofAspergillus fumigatus B 19119 intravenously, a suspension containing 10⁸Candida albicans cells intravaginally and a aqueous suspension ofTrichophyton quinckeanum on lightly scarified dorsal skin. Treatmentwith the test compounds (orally or intravenously) was begun on the dayof infection and continued for 5 days. All animals that diedspontaneously and those that survived and were sacrificed on day 6, weresampled for the numbers of Aspergillus fumigatus CFU/g in kidney andspleen, for skin lesion scores (0=no visible lesion; 1=a few pointlesions; 2=moderate lesions; 3=severe lesions) and for Candida albicansCFU from a vaginal swab.

Mouse Disseminated Candida Model

Mice in groups of 10 were infected intravenously with 8×10⁵ CFU ofCandida albicans. Treatment was begun on the day of infection andrepeated daily for 9 days. Candida albicans CFU/g kidney were measuredfor all mice that died spontaneously or were killed on day 10.

The table indicates the lowest concentrations of the shown compoundsthat achieved a reduction in mean Candida counts of 1 log (i.e. a10-fold reduction) or more, either in the triple mycosis model or thedisseminated Candida infection; also the lowest concentrations thatreduced mean skin scores below 1.0 in the cutaneous dermatophytosiscomponent of this model (NT=nor tested, IV=intravenous).

    ______________________________________                                        Mouse triple mycosis model                                                                          Mouse disseminated                                      Vaginal Candida                                                                            Dermatophyte Candida model                                       CFU reduced  skin score   Kidney Candida CFU                                  by 1 log or more                                                                           reduced to ≦1                                                                       reduced by 1 log or more                            CN  IV route                                                                              oral route                                                                             IV route                                                                            oral route                                                                           IV route                                    ______________________________________                                        34  2.5     2.5      2.5   2.5     5                                          3   2.5     2.5      2.5   2.5    10                                          17  <2.5    NT       <2.5  NT     NT                                          ______________________________________                                    

Example 24 Determination of Fungal Susceptibility

A panel of Candida isolates plus single isolates of the dermatophytesMicrosporum canis, Trichophyton rubrum and T. mentagrophytes;Aspergillus fumigates, and Cryptococcus neoformans were used to evaluatethe activity of the test compounds in vitro. Inocula were prepared asbroth cultures (yeasts) or as suspensions of fungal material made fromagar slope cultures (moulds). The test compounds were pipetted from DMSOstock solution into water to provide a series of 10-fold dilutions. Thefungal inocula were suspended in the growth medium CYG (F.C. Odds,Journal of Clinical Microbiology, 29, (2735-2740, 1991) at approximately50000 colony-forming units (CFU) per ml and added to the aqueous testdrugs.

The cultures were set up in the 96 wells of plastic microdilution platesand they were incubated for 2 days at 37° C. (Candida spp.) or for 5days at 30° C. (other fungi). Growth in the microcultures was measuredby its optical density (OD) measured at a wavelength of 405 nm. The ODfor cultures with test compounds was calculated as a percentage of thecontrol, drug-free OD. Inhibition of growth to 35% of control or lesswas recorded as significant inhibition.

Minimal inhibitory concentration (MICs) of intermediates 15, 16, 17, 18,24 range from ≦0.01 to about 10 μM Candida glabrata, Candida krusei,Candida parapsilosis, nonazole-resistent Candida albicans, Candidakefyr, Microsporum canis, Trichophyton rubrum, Trichophytonmentagrophytes, Cryptococcus neoformans, Aspergillus fumigatus.

E. Composition Examples

"Active ingredient" (A.I.) as used throughout these examples relates toa compound of formula (I), a pharmaceutically acceptable acid additionsalt or a stereochemically isomeric form thereof.

Example 25 Oral Drops

500 Grams of the A.I. was dissolved in 0.5 l of a sodium hydroxidesolution and 1.5 l of the polyethylene glycol at 60°˜80° C. Aftercooling to 30°˜40° C. there were added 35 l of polyethylene glycol andthe mixture was stirred well. Then there was added a solution of 1750grams of sodium saccharin in 2.5 l of purified water and while stirringthere were added 2.5 l of cocoa flavor and polyethylene glycol q.s. to avolume of 50 l, providing an oral drop solution comprising 10 mg/ml ofA.I. The resulting solution was filled into suitable containers.

Example 26 Capsules

20 Grams of the A.I., 6 grams sodium lauryl sulfate, 56 grams starch, 56grams lactose, 0.8 grams colloidal silicon dioxide, and 1.2 gramsmagnesium stearate were vigorously stirred together. The resultingmixture was subsequently filled into 1000 suitable hardened gelatincapsules, comprising each 20 mg of the active ingredient.

Example 27 Film-Coated Tablets Preparation of Tablet Core

A mixture of 100 grams of the A.I., 570 grams lactose and 200 gramsstarch was mixed well and thereafter humidified with a solution of 5grams sodium dodecyl sulfate and 10 grams polyvinylpyrrolidone in about200 ml of water. The wet powder mixture was sieved, dried and sievedagain. Then there was added 100 grams microcrystalline cellulose and 15grams hydrogenated vegetable oil. The whole was mixed well andcompressed into tablets, giving 10.000 tablets, each containing 10 mg ofthe active ingredient.

Coating

To a solution of 10 grams methyl cellulose in 75 ml of denaturatedethanol there was added a solution of 5 grams of ethyl cellulose in 150ml of dichloromethane. Then there were added 75 ml of dichloromethaneand 2.5 ml 1,2,3-propanetriol. 10 Grams of polyethylene glycol wasmolten and dissolved in 75 ml of dichloromethane. The latter solutionwas added to the former and then there were added 2.5 grams of magnesiumoctadecanoate, 5 grams of polyvinylpyrrolidone and 30 ml of concentratedcolour suspension and the whole was homogenated. The tablet cores werecoated with the thus obtained mixture in a coating apparatus.

Example 28 Injectable Solution

1.8 Grams methyl 4-hydroxybenzoate and 0.2 grams sodium hydroxide weredissolved in about 0.5 l of boiling water for injection. After coolingto about 50° C. there were added while stirring 0.05 grams propyleneglycol and 4 grams of the A.I.. The solution was cooled to roomtemperature and supplemented with water for injection q.s. ad 1 l,giving a solution comprising 4 mg/ml of A.I. The solution was sterilizedby filtration and filled in sterile containers.

Example 29 Suppositories

3 Grams A.I. was dissolved in a solution of 3 grams2,3-dihydroxybutanedioic acid in 25 ml polyethylene glycol 400. 12 Gramssurfactant (SPAN®) and triglycerides (Witepsol 555®) q.s. ad 300 gramswere molten together. The latter mixture was mixed well with the formersolution. The thus obtained mixture was poured into moulds at atemperature of 37°-38° C. to form 100 suppositories each containing 30mg/ml of the A.I.

We claim:
 1. A compound of formula (I), ##STR28## a pharmaceutically acceptable acid or base addition salt thereof or a stereochemically isomeric form thereof, whereinA and B taken together form a bivalent radical of formula:--N═CH-- (a), --CH═N-- (b), --CH₂ --CH₂ -- (c), --CH═CH-- (d), --C(═O)--CH₂ -- (e), --CH₂ --C(═O)-- (f),wherein one hydrogen atom in the radicals (a) and (b) may be replaced with a C₁₋₆ -alkyl-radical and up to two hydrogen atoms in radical (c), (d), (e) or (f) may be replaced by a C₁₋₆ -alkyl-radical; D is a radical of formula ##STR29## L is a radical of formula ##STR30## Alk is a C₁₋₄ alkanediyl radical; R¹ is halo; R² is hydrogen or halo; R³ is hydrogen, C₁₋₆ alkyl, phenyl or halophenyl; R⁴ is hydrogen, C₁₋₆ alkyl, phenyl or halophenyl; R⁵ is hydrogen or C₁₋₆ alkyl; R⁶ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkyloxycarbonyl, or R⁵ and R⁶ taken together with the nitrogen atom to which they are attached form a pyrrolidine, piperidine, morpholine, piperazine or substituted piperazine ring, said substituted piperazine being a piperazine ring substituted on the 4-position of the piperazine ring with C₁₋₆ alkyl, hydroxyC₁₋₆ alkyl, aminoC₁₋₆ alkyl, mono- or di(C₁₋₆ alkyl) aminoC₁₋₆ alkyl.
 2. A compound according to claim 1, wherein D is a radical of formula (D₁) or (D₂).
 3. A compound according to claim 2, wherein D is a radical of formula (D₁), wherein R¹ is chloro or fluoro and R² is hydrogen, chloro or fluoro; L is a radical of formula (L₁), wherein R³ and R⁴ each independently are phenyl or hydrogen.
 4. A compound according to claim 3, wherein the compound is (±)-cis-4- 4- 4- 4- 2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl!methoxy!phenyl!-1-piperazinyl!phenyl!-2- 3,3-dimethyl-2-(phosphonooxy)butyl!-2,4-dihydro-3H-1,2,4-triazol-3-one, a stereochemically isomeric form or a base addition salt form thereof.
 5. A composition comprising a pharmaceutically acceptable carrier and as active ingredient an antifungally effective amount of a compound as claimed in claim
 1. 6. A composition comprising a pharmaceutically acceptable carrier and as active ingredient an antifungally effective amount of a compound as claimed in claim
 2. 7. A composition comprising a pharmaceutically acceptable carrier and as active ingredient an antifungally effective amount of a compound as claimed in claim
 3. 8. A composition comprising a pharmaceutically acceptable carrier and as active ingredient an antifungally effective amount of a compound as claimed in claim
 4. 9. A method of inhibiting the development of or eliminating fungi in warm blooded animals suffering from infection by said fungi, which method comprises administering to said warm blooded animals an antifungally effective amount of a compound as claimed in claim
 1. 10. A method of inhibiting the development of or eliminating fungi in warm blooded animals suffering from infection by said fungi, which method comprises administering to said warm blooded animals an antifungally effective amount of a compound as claimed in claim
 2. 11. A method of inhibiting the development of or eliminating fungi in warm blooded animals suffering from infection by said fungi, which method comprises administering to said warm blooded animals an antifungally effective amount of a compound as claimed in claim
 3. 12. A method of inhibiting the development of or eliminating fungi in warm blooded animals suffering from infection by said fungi, which method comprises administering to said warm blooded animals an antifungally effective amount of a compound as claimed in claim
 4. 